EP0657456A1

EP0657456A1 - Process for preparing epibatidine

Info

Publication number: EP0657456A1
Application number: EP94119544A
Authority: EP
Inventors: Chemical Engineer Csaba Szantay Dr.; Dr. chemist Zsuzsanna Balogh née Kardos; Dr. Chemistry Teacher Istvan Moldvai; Dr. chemical engineer Eszter Temesvari née Major; Dr. Chemical Engineer Csaba Szantay Jr.; Dr. Chemical Engineer Attila Mandi; Dr. Chemical Engineer Gabor Blasko; Dr. Chemical Engineer Gyula Simig; Dr. Physician Sandor Drabant; Dr. Physician Tamas Szallasi; Dr. Physician Marton Fekete; Biologist Gabor Gigler
Original assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Current assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Priority date: 1993-12-09
Filing date: 1994-12-09
Publication date: 1995-06-14
Anticipated expiration: 2014-12-09
Also published as: FR2713642B1; BE1009080A4; DE69403615D1; ITMI942485A0; HUT69381A; ITMI942485A1; HU9303505D0; CA2137613A1; US5545741A; EP0657456B1; ATE154022T1; FR2713642A1; KR950017995A; EP0736534A1; JPH07278151A

Abstract

The subject-matter of the invention is a process for preparing racemic or optically active epibatidine of formula

which comprises subjecting racemic or optically active epi-epibatidine of formula

to epimerization in the presence of a base or cyclising a 1-[diacylamino]-2-[6'-chloro)-pyrid-3'-yl]-4-[amino]-cyclohexane of general formula

wherein

Ac: stands for an acyl group.

The advantage of the process is that readily available starting materials are used and the procedure is suitable for industrial scale productions, too.

Description

The invention is concerned with a process for preparing an organic compound, namely epibatidin, i. e. 2-[6'-(chloro)-pyrid-3'-yl]-7-azabicyclo[2.2.1]heptane, of formula

Epibatidine is a minor alkaloid isolated from the skin extracts of an Ecuadoran frog, Epipedobates tricolor, of the familiy Dendrobatidae. Considering the chemical structure it is the first natural substance containing a 7-azabicyclo[2.2.1]heptane skeleton. To the exo position of the said skeleton a 2-(chloro)-pyrid-3-yl substituent is attached, which can rarely be found in nature. The alkaloid possesses a valuable biological property, namely it has 200 times the analgesic potency of morphine. The mechanism of the analgesic effect is different from that of morphine, as it does not subside upon administering morphine antagonists, e.g. 17-(allyl)-4,5α -(epoxy)-3,14-di-(hydroxy)-morphinan-6-one [naloxone] (T. F. Spande, H. M. Garraffo, M. W. Edwards, H. J. C. Yeh, L. Pannell, J. W. Daly: J. Am. Chem. Soc., 1992, 114, 3 475 to 3 478).
Several processes have been disclosed in the literature for the synthetic preparation of epibatidine:

A) Ch. A. Broka: Tetrahedron Letters, 34 [1993], 3 251 to 3 254. In this reaction an adduct was prepared by the Diels-Alder reaction of enal obtained by the homologization of 6-(chloro)-nicotinic aldehyde and 2-(trimethylsilyloxy)-1,3-butadiene, it was then reduced with lithium, sodium and potassium tri-2-butyl borohydride [L-selectride®], the hydroxy group of the product was protected by silylation, while the hydroxymethyl substituent was first converted into the hydroxy group in 6 reaction steps and then benzoylated. By selective removal of the protecting groups the dihydroxy derivative was converted into 4-(mesyloxy)-cyclohexylamine containing a 6-(chloro)-pyridyl substituent, and the boiling of the latter compound in dichloromethane resulted in racemic epibatidine.
B) J. W. Daly, T.F. Spande, H. M. Garraffo: US Dept. Health and Human Service, US 7,845,042-A and WO 93/18037. The key intermediate of this synthesis is 3-(pyridyl)-2-cyclohexa-1,3-diene, which was prepared from cyclohexane-1,2-dione and converted into Diels-Alder adduct with tert.butylnitrosoformiate. The adduct was hydrogenated catalytically, the thus-obtained aminoalcohol was treated with thionyl chloride, the product was cyclized and chlorinated by a photochemical reaction. The hydrolysis of the acid amide bond resulted in racemic epibatidine.
C) D. F. Huang, T. Y. Shen: Tetrahedron Letters, 34 [1993], 4 477 to 4 480. An adduct obtained by the Diels-Alder reaction of phenylsulfonyl-6-(chloro)-6-(pyridyl)-acetylene prepared from N-(carbomethoxy)-pyrrole and 6-(chloro)-nicotinic acid was desulfonated with sodium amalgam, hydrogenated catalytically, the protecting group was dehydrolyzed to obtain racemic epibatidine and racemic epi-epibatidine, which were then separated by column chromatography. The racemic epibatidine was resolved with di-(p-toluyl)-tartaric acid.
D) S. R. Fletcher, R. Baker, M. S. Chambers, S. C. Hobbs, P. J. Mitchell: J. Chem. Soc. Chem. Comm., 1993, 1 216 to 1 218. The key intermediate of this synthesis route is tert.butyloxycarbonyl-7-azabicyclo[2.2.1]heptan-2-one, which was prepared in 7 reaction steps from cyclohexene amine containing a trifluoroacetyl protecting group and reacted with 5-lithio-2-(chloro)-pyridine. From the thus-obtained adduct water was removed and the thus-formed double bond was hydrogenated catalytically to obtain a mixture of racemic epibatidine and epi-epibatidine isomers containing tert.butyloxycarbonyl protecting group. The undesired epimer was subjected to epimerization by boiling in tert.butanol in the presence of potassium tert.butylate. The racemic epibatidine was resolved by applying a chiral HPLC method and by salt formation with a chiral acid.

A serious drawback of the methods known from the literature resides in the cumbersome reaction steps which would make the industrial scale application rather complicated.
A further disadvantage of the known preparation methods resides in the fact that they require the application of difficultly available, expensive and inconvenient substances.
The problem underlying to the invention is to create a novel process for preparing epibatidine, which is devoid of the drawbacks of the hitherto known processes and can be accomplished by using substances readily available and preparable even on an industrial scale and which is also industrially applicable.
The above surprisingly has been attained by the invention.
The subject matter of the invention is a process for preparing racemic or optically active epibatidine of formula

characterized by

a) subjecting racemic or optically active epi-epibatidine of formula
to epimerization in the presence of a base
or
b)
- α) cyclising a racemic or optically active 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula
  wherein
  
  L
  
  stands for a leaving group, particularly a C₁₋₄-alkylsulfonyloxy or arylsulfonyloxy group,
  
  to racemic or optically active epi-epibatidine of formula XIII
  and thereafter
- β) subjecting the latter to epimerization in the presence of a base
  or
c)
- α) selectively reducing the nitro group of 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula
  to yield 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula
- β) protecting the carbonyl group in the latter, preferably to yield a 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula
  wherein
  
  R₁ and R₂
  
  stand for C₁₋₄-alkyl groups or together form a C₂₋₄-alkylene group,
  
  particularly 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one-ethylene ketal of formula
  i. e. the compound of formula XV, in which R₁ and R₂ together form an ethylene group,
- γ) diacylating the amino group of the latter, preferably to yield a 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula
  wherein
  
  R₁ and R₂
  
  stand for C₁₋₄-alkyl groups or together form a C₂₋₄-alkylene group and
  
  Ac
  
  represents an acyl group,
  
  particularly a 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one-ethylene ketal of formula
  wherein
  
  Ac
  
  represents an acyl group,
  
  i.e. the compound of formula XVI, in which R₁ and R₂ together form an ethylene group,
- δ) deprotecting the oxo group of the latter to yield a 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of general formula
  wherein
  
  Ac
  
  stands for an acyl group,
- ε) exchanging in the latter the oxo group for an amino group to yield a 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-4-[amino]-cyclohexane of general formula
  wherein
  
  Ac
  
  stands for an acyl group,
  and
- ω) cyclizing the latter into epibatidine of formula XIV
  or
d) cyclizing 1-[6'-(chloro)-pyrid-3'-yl]-3-[oxo]-6-[nitro]-hexa-1-ene of formula
in the presence of an optically active base to optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV
and thereafter
d₁)
- α) selectively reducing the optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV thus obtained to yield optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula
- β) introducing into the latter a leaving group to yield an optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula
  wherein
  
  L
  
  represents a leaving group, particularly a C₁₋₄-alkylsulfonyloxy or arylsulfonyloxy group,
- γ) reducing the latter to an optically active 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula
- δ) cyclising the latter to an optically active epi-epibatidine of formula XIII
  and
- ε) subjecting the latter to epimerization in the presence of a base
  or
d₂) converting the optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV into an optically active epibatidine of formula XIV analogously to variant c)

Preferably the epimerization of the epi-epibatidine of formula XIII according to variant a) or b), part β) of the process according to the invention is carried out under heating, particularly at the boiling point of the reaction mixture. Preferably using for the epimerization an alkali alcoholate, particularly potassium tert.butylate or sodium ethylate, or another organic alkali compound, particularly a lithium salt of a secondary amine, above all lithium diisopropyl amine, is used. A further example of another organic alkali compound is butyl lithium. Advantageously the epimerization in the presence of an alkali alcoholate is carried out under heating and the epimerization in the presence of an other organic alkali compound at a temperature of about 0°C. It is preferable to carry out the epimerization in a C₁₋₄-alkanol as medium in the presence of an alkali alcoholate corresponding to the alkanol used as solvent.
The epibatidine of formula XIV has a chiral structure so that it can be present in racemic or optically active form. The invention encompasses the preparation of both the racemic and the optically active epibatidine of formula XIV.
The racemic epibatidine of formula XIV can optionally be resolved. The resolution can be carried out by methods known per se. One can proceed e. g. by reacting the racemic epibatidine of general formula XIV with an optically active acid, such as tartaric acid, di-(0,0'-p-toluyl)-tartaric acid or dibenzoyltartaric acid, separating the thus-obtained diastereoisomeric salt pair, e. g. by fractional crystallization and liberating the desired optically active epibatidine of formula XIV from the salt thereof.
In variant b), part α) of the process according to the invention preferably a 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula I, in which the leaving group represented by L is a methanesulfonyloxy, p-toluenesulfonyloxy or p-(bromo)-phenylsulfonyloxy group is cyclized, the methanesulfonyloxy group for L being particularly preferred. Furthermore it is preferred to cyclize the 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula I at an elevated temperature, particularly at the boiling point of the reaction mixture. Advantageously the cyclization is performed in a preferably anhydrous, aprotic solvent. For this purpose particularly halogenated hydrocarbons, most particularly methylene chloride, chloroform or chlorobenzene, or aromatic hydrocarbons, most particularly benzene, toluene or xylene, or a mixture thereof are used. Above all the cyclization is carried out in benzene, toluene and/or xylene as aprotic solvent(s). The cyclization may be carried out under an inert gas atmosphere, e. g. under argon. The epi-epibatidine of formula XIII thus obtained can be isolated from the reaction mixture by cooling the latter to room temperature, shaking it with an aqueous alkali hydroxide solution, separating the phases, extracting the aqueous phase with an appropriate organic solvent, for example, dichloromethane, and washing, drying and evaporating the combined organic phases. The thus obtained epi-epibatidine of formula XIII is optionally purified by crystallization or column chromatography.
In variant c), part α) of the process according to the invention the selective reduction of the nitro group of 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV to yield the 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula XIX may be carried out by catalytic hydrogenation or reduction with a chemical agent.
When a chemical reducing agent is used, preferably the selective reduction of the nitro group of 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV is carried out by Bechamps reduction, or with zinc in glacial acetic acid or with zinc, iron or tin in hydrochlorid acid or with stannous (II)-chloride the latter being particularly preferred. One may work preferably by using stannous(II)-chloride in a polar organic solvent, e. g. a C₁₋₄-alkanol or tetrahydrofurane, or a mixture of such. Chemical reduction may be performed in a neutral medium as well. The selective reduction having been completed the reaction mixture may be evaporated.
Preferably in variant c), part β) of the process according to the invention protecting of the carbonyl group in the 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl)-cyclohexane-4-one of formula XIX is made in the form of an ethylene ketale thus yielding 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ethylene ketal of formula XVa. Advantageously this reaction is carried out by dissolving the evaporation residue above obtained in an apolar organic solvent non miscible with water, e. g. benzene or toluene, benzene being preferred, or a mixture of such, adding a monohydric C₁₋₄-alcohol or dihydric C₂₋₄-alcohol, e. g. methanol, ethanol, ethylene glycol or an ortho formic acid ester, ethylene glycol being preferred, and heating the reaction mixture to boiling in the presence of an inorganic or organic acid or a salt thereof, preferably pyridinium tosylate. The 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula XV, particularly 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ethylene ketal of formula XVa, thus obtained can be isolated in a known manner. Thus one may proceed by cooling the reaction mixture, separating the layers, making the benzene phase alkaline, washing with water and saturated brine, drying and evaporating. The ethylene glycol layer is made alkaline, the precipitated product is filtered, to the filtrate water is added and it is extracted with an organic solvent non miscible with water, e. g. a chlorinated hydrocarbon, preferably chloroform. The organic phase is washed, dried and evaporated. The evaporated residue thus obtained is combined with the evaporation residue of the benzene phase. The 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula XV, particularly 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ethylene ketal of formula XVa, thus obtained may be purified by column chromatography.
In variant c), part γ) of the process according to the invention preferably the diacylation of the amino group of the 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula XV is carried out to yield a 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula XVI, in which Ac stands for C₁₋₄-alkylsulfonyl or arylsulfonyl, particularly methanesulfonyl, p-toluenesulfonyl or p-(bromo)-phenylsulfonyl. Thus it is preferred to use an acylating agent containing a sulfonyl group, e. g. p-toluene sulfonyl chloride, p-(bromo)-phenyl sulfonyl chloride, trifluoromethane sulfonyl chloride or methane sulfonyl chloride. Advantageously this diacylation is carried out by dissolving the 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula XV in a polar aprotic solvent, e. g. dimethyl formamide, and reacting it with an acylating agent in the presence of an organic base, e. g. triethyl amine and/or sodium hydride, at room temperature. If desired, the diacylation of the amino group may be carried out by first monoacylating and thereafter introducing the second acyl group into the monoacylated product. The 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula XVI may be isolated from the reaction mixture by methods known per se. Thus one may proceed e. g. by pouring the reaction mixture into water, removing the precipitate by filtration, washing and drying. The 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula XVI thus obtained may be purified by recrystallization or column chromatography, if desired.
Preferably in variant c), part δ) of the process according to the invention the deprotection of the oxo group of the 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula XVI to yield a 1-[di-acylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of general formula XVII is carried out by acidic treatment. This removal of the protecting group of the oxo group may be carried out by methods known per se. Thus the 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula XVI may be dissolved in an organic solvent with 1 to 4 carbon atom(s) and containing an oxo group, e. g. acetone, and heated to boiling in the presence of an organic or inorganic acid, preferably concentrated hydrochloric acid. One may proceed preferably by continuously distilling off acetone from the system and adding acetone dropwise to the reaction mixture at the same rate as acetone is removed. The 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of general formula XVII may be isolated in a known manner. Thus one may proceed by cooling and evaporating the reaction mixture and adding a solvent non-miscible with water, e. g. a chlorinated hydrocarbon, preferably chloroform, and a sodium hydroxide solution to the mixture. The layers are separated, the aqueous phase is extracted with chloroform, the combined organic phases are washed, dried and evaporated. The 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of general formula XVII may be purified by crystallization or column chromatography, if desired.
Preferably in variant c), part ε), of the process according to the invention the exchange of the oxo group of the 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of general formula XVII for an amino group is carried out by reduction with a complex metal hydride in the presence of ammonium acetate. Particularly lithium cyano borohydride and/or sodium cyanoborohydride is/are used as complex metal hydride(s), above all the latter one. Advantageously this reaction may be performed by dissolving the 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of general formula XVII in an anhydrous C₁₋₄-alkanol, preferably methanol, and carrying out the reduction in this. The reaction is preferably carried out at room temperature. The 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-4-[amino]-cyclohexane of general formula XVIII thus obtained may be isolated in a manner known per se. Thus one may proceed by decomposing the excess of the reducing agent by adding an organic solvent containing an oxo group, e. g. acetone, evaporating the reaction mixture, dissolving the residue in an organic solvent non-miscible with water and washing, drying and evaporating the organic phase. The 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-4-[amino]-cyclohexane of general formula XVIII thus obtained may be purified by crystallization or column chromatography, if desired.
Preferably in variant c), part ω) of the process according to the invention the cyclization of the 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-4-[amino]-cyclohexane of general formula XVIII, to yield epibatidine of formula XIV is carried out by heating, particularly to boiling, in [an] organic solvent(s). Particularly preferably for the cyclization as organic solvent(s) [an] anhydrous dipolar aprotic solvent(s), most preferably dimethyl formamide, is/are used. Furthermore it is preferred to carry out the cyclisation in the presence of sodium borohydride. The epibatidine of formula XIV thus obtained may be isolated by methods known per se. Thus one may proceed by pouring the reaction mixture into water and separating the epibatidine of formula XIV by filtration or extraction. The epibatidine of formula XIV may be purified by crystallization or column chromatography, if desired.
The optically active forms of epibatidine of formula XIV may be prepared by several methods.
According to variant d) of the process according to the invention 1-[6'-(chloro)-pyrid-3'-yl)-3-[oxo]-6-[nitro]-hexa-1-ene of formula V is subjected to cyclisation in the presence of an optically active base to yield an optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV. As optically active base preferably (+)-α-(phenyl)-ethyl-amine or (-)-α-(phenyl)-ethyl-amine is used. The reaction may be carried out in the presence of an inert organic solvent, preferably an ether, e. g. tetrahydrofurane or dioxane, or a mixture of such.
In variant d₁), part α) of the process according to the invention the selective reduction of the 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV to the 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula III is preferably carried out with complex metal hydrides. As reducing agent particularly sodium borohydride or lithium, sodium and potassium tri-2-butyl borohydride [L-selectride®] is applied. The reduction with sodium borohydride proved to be most particularly preferable. When sodium borohydride is applied as reducing agent the reduction is preferably performed in a C₁₋₄-alcohol, particularly ethanol. Advantageously one proceeds under cooling, preferably at a temperature of about 0°C. When the reaction has been accomplished the excess of the reducing agent may be decomposed by the addition of a solvent containing an oxo group, e. g. acetone, the solvent removed and the hydroxy compound 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula III isolated by dissolving the evaporation residue in a solvent non-miscible with water, e. g. a halogenated hydrocarbon, particularly chloroform, aromatic hydrocarbon, ether, or ethyl acetate, or a mixture of such and washing, drying and evaporating the organic phase. The 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula III thus obtained is optionally purified by crystallization or chromatography.
Preferably in variant d₁), part β) of the process according to the invention the introduction of the leaving group into the optically active nitroalcohol 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula III thus obtained to yield a 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula II is carried out with the corresponding sulfonyl halide, particularly methanesulfonyl chloride. The acylating agent is preferably applied in excess. The reaction can be carried out in an apolar aprotic solvent, e. g. halogenated hydrocarbon, such as dichloromethane or chloroform, or a mixture of such in the presence of a base, e. g. pyridine. It is preferable to perform the reaction in a mixture of dichloromethane and pyridine. The reaction can be carried out at a temperature of about room temperature. The 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula II thus obtained can be isolated from the reaction mixture by removing the solvent, dissolving the residue in an organic solvent non-miscible with water, e. g. halogenated hydrocarbon, particularly chloroform, aromatic hydrocarbon, ether or ethyl acetate, or a mixture of such, extracting the solution with an inorganic base, e. g. alkali carbonate, extracting the aqueous solution with the organic solvent non-miscible with water which has been previously used and washing, drying and evaporating the combined organic phases. The thus-obtained 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula II can optionally be purified by crystallization or column chromatography.
Advantageously in variant d₁), part γ) of the process according to the invention the reduction of the optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula II to the optically active 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl)-cyclohexane, 4-substituted by a leaving group of formula I is carried out according to the preferences for variant c), part α) of the process according to the invention.
In variant d₁), part δ) of the process according to the invention advantageously the cyclization of the optically active 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of formula I to the optically active epi-epibatidine of formula XIII is carried out according to the preferences for variant b), part α) of the process according to the invention.
The optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV may be converted into optically active epibatidine of formula XIV in an analogous manner to that disclosed above as variant c) in connection with the preparation of racemic epibatidine of formula XIV this being variant d₂) of the process according to the invention.
The still achiral but prochiral 1-[6'-(chloro)-pyrid-3'-yl]-3-[oxo]-6-[nitro]-hexa-1-ene of formula V may be converted into an optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV by means of an enantioselective synthesis. The optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV can be transformed into a dextro or laevo rotating epibatidine of formula XIV with the aid of the synthesis steps described above as variant c) for the preparation of racemic epibatidine.
Optically active epibatidine of formula XIV can also be prepared by separating racemic epibatidine of formula XIV into the optically active isomers or subjecting a racemic intermediate at a suitable stage of the synthesis to resolution and converting the optically active intermediate thus obtained into optically active epibatidine of formula XIV.
According to a preferred embodiment of the above process racemic epi-epibatidine of formula XIII is subjected to resolution. The process may be carried out by reacting racemic epi-epibatidine of formula XIII with an optically active acid, e. g. optically active tartaric acid, dibenzoyl-tartaric acid or di-0,0'-(p-toluyl)-tartaric acid, separating the diastereoisomeric salts thus formed, e. g. by fractionated crystallization, and liberating the optically active epi-epibatidine of formula XIII from the salt thereof. Then one may proceed to epimerisation of the latter according to variant a) of the process according to the invention.
According to a further embodiment of the process according to the invention another intermediate of chiral structure is subjected to resolution and the optically active intermediate thus obtained is converted into the desired optically active end-product optically active epibatidine of formula XIV in an analogous manner to the process described above for the preparation of racemic epibatidine of formula XIV.
Thus according to a preferred embodiment of the invention optically active epibatidine of formula XIV may be prepared by carrying out the variant d₁) or d₂) of the process according to the invention with the optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV as above described.
Moreover one may proceed preferably by subjecting the racemic nitro alcohol 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula III to resolution and carrying out the further steps of the synthesis by using the optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula III thus obtained. The racemate of 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula III is separated into the optically active isomers preferably by acylating the racemic 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula III with optically active menthyl-chloro-formiate (chloro-formic acid menthyl ester), separating the diastereomers thus formed by crystallization and thereafter removing the menthyl group to yield the desired optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula III. The further reactions may be according to variant d₁), parts β), γ), δ) and ε) of the process according to the invention indicated above with the preferences described with regard to these.
The 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexanes, 4-substituted by a leaving group, of general formula I used as starting substances in variant b) of the process according to the invention could have been prepared by selectively reducing the nitro group of 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula II. Advantageously this reaction is performed by catalytic hydrogenation or reduction with a chemical agent. Preferably this selective reduction is carried out by Bechamps-reduction, or with zinc in glacial acetic acid or with zinc, iron or tin in hydrochloric acid or with stannous(II)-chloride the latter being particularly preferred. The reduction with stannous(II)-chloride is preferably carried out in a polar organic solvent, e. g. C₁₋₄-alcohol, particularly ethanol, or tetrahydrofurane, or a mixture of such. The chemical reduction can also be carried out in a neutral reaction medium. The reduction reaction with stannous(II)-chloride can be carried out under heating, preferably at the boiling point of the reaction mixture. The thus obtained 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula I can be isolated from the reaction mixture by cooling the mixture to room temperature and adding a solvent non-miscible with water, e. g. a chlorinated hydrocarbon, preferably chloroform, or a mixture of such to it and rendering the solution slightly alkaline. The separated precipitate is filtered off, washed with a solvent non-miscible with water and the organic phases are combined, washed, dried and evaporated. The thus-obtained 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula I is optionally purified by crystallization or column chromatography.
The starting substances of 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexanes, 4-substituted by a leaving group, of general formula II for preparing the above starting substances could be prepared as specified below.
A particular advantage of the synthesis resides in the fact that 1-(nitro)-pentane-4-one of formula

is used as starting substance, which can be obtained by reacting commercially readily available compounds, that is nitromethane of formula

H₃C - NO₂ XII

and methylvinylketone of formula

The 1-(nitro)-pentan-4-one of formula X can be produced according to the method of D. E. Bergbreiter and J. J. Lalonde (J. Org. Chem. 52 [1987], 1 601 to 1 603).
In the next reaction step the 1-(nitro)-pentane-4-one of formula X is brominated. Preferably the bromination is carried out with elementary bromine in a lower alcohol, particularly methanol. Conveniently the bromination is performed at a temperature of about room temperature taking care of that the temperature of the reaction mixture should not rise above 40°C. The acetalic ether bond being formed in the reaction is hydrolyzed. The 1-(bromo)-5-(nitro)-pentane-2-one of formula

thus obtained may be isolated by extracting the aqueous solution with a solvent non-miscible with water such as chlorinated hydrocarbon, aromatic hydrocarbon, ethyl acetate or preferably ether, washing the extract first acid-free with a caustic solution then neutral with water, dried and evaporated. The 1-(bromo)-5-(nitro)-pentane-2-one of general formula IX is optionally purified by column chromatography.
The 1-(bromo)-5-(nitro)-pentane-2-one of formula IX is then reacted with a triaryl phosphine to obtain a phosphonium salt [5-(nitro)-pentane-2-one]-triaryl-phosphonium bromide of general formula

wherein

Ar: stands for an aryl group, preferably phenyl group.

The phosphonium salt [5-(nitro)-pentane-2-one]-triaryl-phosphonium bromide of general formula VIII is then converted into a [5-(nitro)-pentane-2-one]-triaryl-phosphorane, preferably [5-(nitro)-pentane-2-one]-triphenyl-phosphorane, of general formula

wherein

Ar: stands for an aryl group, preferably phenyl group.

The [5-(nitro)-pentane-2-one]-triaryl-phosphorane, preferably [5-(nitro)-pentane-2-one]-triphenyl-phosphorane, of general formula VII thus obtained is reacted with 6-(chloro)-pyridine-3-aldehyde [6-(chloro)-nicotinic aldehyde] of formula

The reaction can be performed in an anhydrous aprotic solvent, preferably a halogenated aliphatic hydrocarbon, such as dichloromethane, or a mixture of such. The reaction can be carried out under heating, preferably at the boiling point of the reaction mixture. It is preferable to perform the reaction by adding to the solution of the [5-(nitro)-pentane-2-one]-triaryl-phosphorane, preferably [5-(nitro)-pentane-2-one]-triphenyl-phosphorane, of general formula VII in an anhydrous aprotic solvent the solution of the 6-(chloro)-pyridine-3-aldehyde of formula VI in the same solvent. The reaction mixture is then preferably worked up by cooling, washing and evaporating. The olefine 1-[6'-(chloro)-pyrid-3'-yl]-3-(oxo)-6-(nitro)-hexa-1-ene of formula

thus obtained can be purified by crystallization or column chromatography.
The 6-(chloro)-pyridine-3-aldehyde of formula VI could be prepared readily from the commercially available 6-(chloro)-nicotinic acid by methods known from the literature (F. E. Ziegler, J. G. Sweeny: Tetrahedron Letters, [1969], 1 097 to 1 110).
The olefine 1-[6'-(chloro)-pyrid-3'-yl]-3-(oxo)-6-(nitro)-hexa-1-ene of formula V obtained as specified above is then subjected to cyclization. This reaction may be carried out in an anhydrous aprotic organic solvent. As reaction medium preferably cyclic ethers, e. g. tetrahydrofuran, or a mixture of such can be applied. The cyclization is preferably carried out in the presence of a base, particularly potassium fluoride applied onto a basic aluminum oxide carrier (D. E. Bergbreiter, J. J. Lalonde: J. Org. Chem. 52 [1987], 1 601 to 1 603). The cyclization may be carried out at a temperature of about room temperature. The thus-obtained nitroketone 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV may be isolated by removing the base and evaporating the solution. Optionally the 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV thus obtained can be purified by crystallization or column chromatography.
The further reactions are as those of variant d₁), parts α), β) and γ) of the process according to the invention with the preferences indicated there also including the racemic substances.
As results therefrom simultaneously part of this synthesis of the starting substances 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexanes, 4-substituted by a leaving group, of formula I for variant b) of the process according to the invention is the synthesis of the starting substance 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexanes-4-one of formula IV for variant c) of the process according to the invention and for the synthesis of the starting substance 1-[6'-(chloro)-pyrid-3'-yl]-3-[oxo]-6-[nitro]-hexa-1-ene of formula V.
The invention is illustrated in detail with the aid of the following Examples. In these the ratios of the components of the mixtures for chromatography are always by volume. Moreover in the following Examples unless other indications have been made column chromatography is to be meant as having been carried out on silica gel with the designation "Kieselgel 60" (0.063 to 0.200 mm). Furthermore "brine" is a saturated sodium chloride solution. For the potassium fluoride precipitated on aluminum oxide always the total amount of these 2 substances and the potassium fluoride contents thereof have been indicated.
The invention claimed also comprises in a manner known per se converting the free epibatidine of formula XIV into an acid addition salt, particularly hydrochloride salt, and/or liberating the free epibatidine of formula XIV from an acid addition salt of it and/or converting it into another acid addition salt thereof.

Example 1

(±)-Epibatidine

Step 1

(±)-Epi-epibatidine

1.1 g (0.0036 mole) of (±)-1α-[amino]-2β-[6'-(chloro)-pyrid-3'-yl]-4β-[methanesulfonyloxy]-cyclohexane prepared as indicated below are dissolved in 150 ml of anhydrous toluene and the reaction mixture is heated to boiling under argon overnight. The reaction mixture is then cooled, 25 ml of a 5% by weight sodium hydroxyde solution are added, the phases are thoroughly shaken, the layers are separated. The aqueous phase is extracted ten times with 20 ml of dichloromethane each. The combined organic layers are washed twice with 100 ml of water each and 100 ml of a saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is subjected to chromatography on a silica column and eluted with a 1:1 mixture of chloroform and methanol. Thus 350 mg of the desired compound are obtained, yield 46%, faint yellow oil. R_f = 0.35 (1:1 mixture of chloroform and methanol).
IR_(film): 3260, 3220, 1580, 1560, 1760, 1200, 1100 cm⁻¹.
The (±)-1α-[amino]-2β-[6'-(chloro)-pyrid-3'-yl]-4β-[methanesulfonyloxy]-cyclohexane used as starting substance has been prepared as follows.

a)

1-(Bromo)-5-(nitro)-pentane-2-one

80.0 g (0.61 mole) of 1-(nitro)-pentane-4-one are dissolved in 250 ml of anhydrous methanol, whereupon 31.5 ml (0.61 mole) of bromine are quickly added under cooling with ice. The reaction mixture is stirred for a further 2 hours at a rate that the internal temperature should not exceed 40°C. To the reaction mixture 250 ml of water are added, the reaction mixture is stirred at room temperature overnight. Next morning the solution is extracted three times with 300 ml of ether each, the ethereal solution is washed with a 10% by weight aqueous sodium carbonate solution free of acid, whereupon it is washed three times with 200 ml of water each and 200 ml of a saturated sodium chloride solution, dried over calcium chloride and evaporated. The dry residue is subjected to chromatography on a silica column and eluted with a 3:1 mixture of n-hexane and ethyl acetate. Thus 70.4 g of the desired compound are obtained in the form of a faint yellow liquid, yield 55%. R_f = 0.30.
IR_(film): 2950, 1720, 640 cm⁻¹.

b)

[5-(Nitro)-pentane-2-one]-triphenyl-phosphonium bromide

10.25 g (0.048 mole) of the bromine compound 1-(bromo)-5-(nitro)-pentane-2-one prepared according to section a) are dissolved in 30 ml of anhydrous benzene whereupon a solution of 14.09 g (0.0537 mole) of triphenyl phosphine in 50 ml of anhydrous benzene is added dropwise. The reaction mixture is stirred at room temperature for 48 hours whereby the oily precipitate becomes crystalline. The precipitated salt is filtered and washed with n-hexane. Thus 20.5 g of the desired compound are obtained,
yield 89%, mp.: 70-72°C.

c)

[5-(Nitro)-pentane-2-one]-triphenyl-phosphorane

8.1 g (0.0171 mole) of the phosphonium salt [5-(nitro)-pentane-2-one]-triphenyl-phosphonium bromide prepared according to section b) are dissolved in 160 ml of dichloromethane and the solution formed is stirred with 136 ml (0.0542 mole) of a 1% by weight aqueous sodium hydroxide solution for 30 minutes. The two phases are separated, the dichloromethane layer is washed three times with 100 ml of water each and with 100 ml of a saturated sodium chloride solution, dried over calcium chloride and evaporated. The dry residue is thoroughly triturated with n-hexane. Thus 4.8 g of the desired compound are obtained, yield 72%, mp.: 94-97°C.

d)

1-[6'-(Chloro)-pyrid-3'-yl]-3-[oxo]-6-[nitro]-hexa-1-ene

To a solution of the 13.5 g (0.0344 mole) of the [5-(nitro)-pentane-2-one]-triphenyl-phosphorane prepared according to section c) in 70 ml of anhydrous dichloromethane a solution of 3.1 g (0.022 mole) of 6-(chloro)-pyridine-3-aldehyde in 70 ml of anhydrous dichloromethane is added. The reaction mixture is heated to boiling for 8 hours in argon atmosphere. The reaction mixture is cooled, the dichloromethane solution is washed subsequently three times with 150 ml of water each and 150 ml of a saturated sodium chloride solution, dried over calcium chloride and evaporated. The dry residue is subjected to chromatography on a silica column and eluted with a 1:1 mixture of n-hexane and ethyl acetate. Thus 4.7 g of the pure desired compound are obtained, yield 84%. Mp.: 97-100°C. R_f = 0.52.
IR_(KBr): 1700, 1680, 1620, 1580, 1550, 1100 cm⁻¹.

e)

(±)-1α-[Nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one

1.6 g (0.0063 mole) of 1-[6'-(chloro)-pyrid-3'-yl]-3-[oxo]-6-[nitro]-hexa-1-ene prepared according to section d) are dissolved in 50 ml of anhydrous tetrahydrofurane whereupon 4.0 g (0.089 mole) of potassium fluoride precipitated on aluminum oxide containing 0.0117 mole of potassium fluoride are added. The reaction mixture is stirred at room temperature overnight. The solid product is filtered, washed with 300 ml of ethyl acetate. The combined filtrates are dried over calcium chloride and evaporated. The residue is purified by chromatography on a silica column and elution with a 1:1 mixture of n-hexane and ethyl acetate. Thus 1.1 g of the pure desired product are obtained, yield 59%.
Mp.: 118-121°C.
R_f = 0.38. IR_(KBr): 1710, 1585, 1550, 1100 cm⁻¹.

f)

(±)-1α-[Nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4β-ol

2.8 g (0.0110 mole) of (±)-1α-[nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one prepared according to section e) are dissolved in 200 ml of anhydrous ethanol whereupon 1.2 g (0.0317 mole) of sodium borohydride are added within a period of about one hour and a half in small portions. The excess of the reducing agent is decomposed by careful addition of acetone, the reaction mixture is evaporated in vacuo, the solid residue is dissolved in a mixture of 50 ml of water and 200 ml of chloroform, the mixture is thoroughly shaken and the layers are separated. The aqueous phase is extracted three times with 200 ml of chloroform each. The combined organic layers are washed twice with 200 ml of water each and 100 ml of a saturated sodium chloride solution, dried over calcium chloride and evaporated. Thus 1.9 g of the desired compound are obtained, yield 67%, mp.: 149-153°C.
IR_(film): 3380, 1580, 1570, 1550, 1100, 1080 cm⁻¹.
R_f = 0.42 (10 : 1 mixture of chloroform and methanol).

g)

(±)-1α-[Nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-4β-[methanesulfonyloxy]-cyclohexane

1.0 g (0.003896 mole) of (±)-1α-[nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4β-ol prepared according to section f) are dissolved in a mixture of 15 ml of anhydrous dichloromethane and 30 ml of pyridine, whereupon 0.75 ml (0.0097 mole) of methanesulfonyl chloride is added dropwise under cooling with icecold water. The reaction mixture is stirred at room temperature overnight and thereafter the solvent is removed in vacuo. The dry residue is dissolved in a mixture of 50 ml of chloroform and 25 ml of a 10% by weight sodium carbonate solution, the mixture is thoroughly shaken, the phases are separated. The aqueous phase is extracted three times with 50 ml of chloroform each. The combined organic layers are washed three times with 100 ml of water each and 100 ml of a saturated sodium chloride solution, dried over calcium chloride and evaporated. The dry residue is subjected to chromatography on a silica column and eluted with a 1:1 mixture of n-hexane and ethyl acetate. Thus 1.18 g of the desired compound are obtained, yield 91%, mp.: 120-122°C.
R_f = 0.46
IR_(KBr): 1590, 1570, 1540, 1530, 1450, 1350, 1180, 1090 cm⁻¹.

h)

(±)-1α-[Amino]-2β-[6'-(chloro)-pyrid-3'-yl]-4β-[methanesulfonyloxy]-cyclohexane

1.5 g (0.0048 mole) of (±)-1α-[nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-4β-[methanesulfonyloxy]-cyclohexane prepared according to section g) are dissolved in 150 ml of ethanol whereupon 10.76 g (0.0477 mole) of stannous(II)-chloride dihydrate are added. The reaction mixture is heated to boiling for 24 hours, whereupon it is cooled, 200 ml of chloroform are added and the pH is adjusted to 9 by adding a concentrated ammonium hydroxide solution. The precipitated product is filtered, washed with 400 ml of chloroform, the organic phase is washed twice with 200 ml of water and once with 200 ml of a saturated sodium chloride solution, dried over magnesium sulfate and evaporated. Thus 1.1 g of the desired compound are obtained in the form of a colourless oil, yield 80%.
R_f = 0.69 (chloroform : methanol = 10 : 1).

Step 2

(±)-Epibatidine

20 mg (0.09 mmole) of epi-epibatidine prepared according to step 1 are boiled in 3 ml of anhydrous tert.butanol in the presence of 100 mg of potassium tert.butylate for 30 hours. After evaporation the product is purified by chromatography on a silica gel column (eluent: 1:1 mixture of benzene and methanol).
Yield: 10 mg (50%), R_f = 0.25.

Example 2

(±)-Epibatidine

Step 1

(±)-1α-[Amino]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one

2.54 g (0.01 mole) of (±)-1α-[nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one prepared as described in the preparation of the starting substance of Example 1, sections a) to e) are dissolved in 250 ml of ethanol, whereupon 27.0 g (0.01 mole) of stannous(II)-chloride dihydrate are added and the reaction mixture is heated to boiling for 24 hours. The solution is evaporated to dryness to yield the desired compound.

Step 2

(±)-1α-[Amino]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one-ethylene glycol

To the residue containing (±)-1α-[amino]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one prepared according to step 1 50 ml of ethylene glycol, 250 ml of benzene and 2.5 g of pyridinium tosylate are added. The reaction mixture is heated to boiling until no more water escapes (about 6 hours). The reaction mixture is cooled, the two layers are separated, the benzene and ethylene glycol layers are separately made alkaline by adding a concentrated ammonium hydroxide solution (to pH 9). The benzene phase is washed three times with 150 ml of saturated brine each and dried over magnesium sulfate. The ethylene glycol phase is filtered, the precipitate is thoroughly washed with 500 ml of chloroform. To the filtrate 300 ml of water are added, it is extracted five times with 200 ml of chloroform each, the combined organic phases are washed twice with 300 ml of saturated brine each and dried over magnesium sulfate. The chloroform and benzene layers are combined and evaporated. The residue is purified on a silica column by eluting with a 10:1 mixture of chloroform and methanol. Thus 1.79 g of the pure desired compound are obtained in the form of a colourless foam, yield 67%, R_f = 0.34.

Step 3a

(±)-1α-[Tosylamino]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one-ethylene ketale

2.0 g (0.007442 mole) of (±)-1α-[amino]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one-ethylene ketale prepared according to step 2 are dissolved in 60 ml of anhydrous dimethyl formamide, whereupon 2.1 ml (0.01506 mole) of triethyl amine and 2.84 g (0.01488 mole) of p-toluenesulfonyl chloride are added. The reaction mixture is stirred at room temperature for an hour and poured into 500 ml of icecold water. The precipitated product is filtered, dried and recrystallized from ethanol. Thus 2.2 g of the desired compound are obtained, yield 69.9%, mp.: 182-184°C.
R_f = 0.36.

Step 3b

(±)-1α-[Ditosylamino]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one-ethylene ketale

4.4 g (0.0104 mole) of (±)-1α-[tosylamino]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one-ethylene ketale prepared according to step 3a) are dissolved in 250 ml of anhydrous dimethyl formamide, whereupon 1.5 g (0.0312 mole) of sodium hydride are added in small portions. The reaction mixture is stirred at room temperature for an hour, 5.95 g (0.0312 mole) of p-toluene-sulfonyl chloride are added and stirring is continued for 2 hours. The reaction mixture is poured into 2 l of icecold water, the precipitated product is filtered, dried and the residue is purified on a silica column by eluting with a 1:1 mixture of n-hexane and ethyl acetate. Thus 4.6 g of the pure desired compound are obtained, yield 57%, mp.: 210-213°C, R_f = 0.39.

Step 4

(±)-1α-[Ditosylamino]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one

4.0 g (0.006931 mole) of (±)-1α-[ditosylamino]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one-ethylene ketale prepared according to step 3b) are dissolved in 200 ml of acetone whereupon 10 ml of concentrated hydrochlorid acid are added. The reaction mixture is heated to boiling for 4 hours at such a rate that the acetone distilled off is continuously replaced by adding dropwise fresh acetone. The reaction mixture is cooled, dissolved in 200 ml of chloroform and the pH is adjusted to 9 by adding a 10% by weight sodium hydroxide solution. The two phases are thoroughly shaken together, the aqueous layer is extracted twice with 100 ml of chloroform each. The chloroform solution is washed twice with 200 ml of water each and once with 200 ml of saturated brine, dried over magnesium sulfate and evaporated. The dry residue is purified on a silica column with a 10:1 mixture of benzene and methanol. Thus 1.55 g of the pure desired compound are obtained in the form of a colourless foam, yield 42%, R_f = 0.53.

Step 5

(±)-4β-[Amino]-1α-[ditosylamino]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane

200 mg (0.3751 millimole) of (±)-1α-[ditosylamino]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one prepared according to step 4 are suspended in 30 ml of anhydrous methanol, whereupon 289 mg (3.751 millimoles) of ammonium acetate, 24 mg (0.3751 millimole) of sodium cyanoborohydride and 16 mg (0.3751 millimole) of lithium chloride are added. The reaction mixture is stirred at room temperature for 2 hours whereupon the excess of the reducing agent is decomposed by adding a few drops of acetone and the solution is then evaporated. The dry residue is dissolved in 20 ml of chloroform and 10 ml of water, the two phases are separated and the aqueous layer is extracted twice with 10 ml of chloroform each. The combined organic solutions are washed once with 10 ml of water and once with 10 ml of saturated brine, dried over magnesium sulfate and evaporated. The dry residue is purified on a silica column and eluted with a 5:1 mixture of chloroform and methanol. Thus 116 mg of the pure desired compound are obtained, yield 58%, mp.: 158-162°C. R_f = 0.18.

Step 6

(±)-Epibatidine

100 mg (0.1872 millimole) of (±)-4β-[amino]-1α-[ditosylamino]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane prepared according to step 5 are dissolved in 10 ml of anhydrous dimethylformamide, whereupon 100 mg (2.64 millimoles) of sodium borohydride are added and the reaction mixture is heated to boiling for 3 hours. After cooling the solution is poured into 25 ml of water and extracted five times with 10 ml of chloroform each. The chloroform layer is washed twice with 20 ml of water each and once with 20 ml of saturated brine, dried over magnesium sulfate and evaporated. The dry residue is purified on a silica column with a 1:1 mixture of chloroform and methanol. Thus 15 mg of the pure desired compound are obtained, yield 38%. The spectrum of the product corresponds to that of racemic epibatidine.

Example 3

Step 1

(-)-1α-[Nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one

5.0 g (0.01963 mole) of 1-[6'-(chloro)-pyrid-3'-yl]-3-[oxo]-6-[nitro]-hexa-1-ene prepared as described in the preparation of the starting substance of Example 1, sections a) to d) are dissolved in 50 ml of anhydrous tetrahydrofurane, whereupon 12.6 ml (0.09815 mole) of (+)-α-(phenyl)-ethyl-amine are added. The reaction mixture is allowed to stand at room temperature for 3 days, whereupon the solution is evaporated. The product is purified by subjecting the crude product to chromatography on a silica column and eluting first with a 10:1 mixture of benzene and methanol (R_f = 0.38) and thereafter with a 1:1 mixture of n-hexane and ethyl acetate (R_f = 0.42). The product is crystallized from ethanol. Thus 1.45 g of the pure desired compound are obtained, yield 29%, mp.: 149-151°C, (α) $\binom{ν}{O}$
= -86.2° (c=2, chloroform).

Further steps

The (-)-1α-[nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one prepared according to step 1 was converted into the corresponding epibatidine by working analogously to Example 2 starting with reacting the former instead of (±)-1α-[nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one.

Example 4

Step 1

(-)-1α-[Nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4β-yl-carbonic acid menthyl ester

1.536 g (6 millimoles) of racemic (±)-1α-[nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4β-ol prepared as described in the preparation of the starting substance of Example 1, sections a) to f) are dissolved in a mixture of 30 ml of anhydrous dichloromethane and 1.4 ml of pyridine at room temperature. To the solution 3.0 ml (14 millimoles) of (-)-menthyl-chloro-formiate (Aldrich 24,530-5) are added dropwise. The reaction mixture is stirred at room temperature for 6 hours, whereupon further 0.2 ml of the reactant is added. The reaction mixture is allowed to stand overnight and then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 60 ml of chloroform and 5 ml of water. The pH of the aqueous layer is adjusted to 9 with a 5% by weight sodium hydrogen carbonate solution. The layers are separated, the chloroform solution is washed three times with 20 ml of water each, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is crystallized from 100 ml of methanol under clarification with charcoal. Thus 1.2 g of the desired compound are obtained in the form of white crystals, yield 45.8%, mp.: 98-100°C, [α]_D²⁵ = -56.0° (c = 0.5, chloroform).
The product thus obtained is further purified by column chromatography (Merck 9385 silicagel, water pump vacuo; eluent = benzol : ethyl acetate = 19:1). The fractions containing the desired compound are evaporated. Thus 630 mg of an oil are obtained which is crystallized from methanol. Thus 280 mg of the desired compound are obtained, mp.: 183-184°C, [α]_D²⁵ = -36.7° (c = 0.5 chloroform).

Step 2

(+)-1α-[Nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4β-ol

100 mg of the crystalline substance (-)-1α-[nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4β-yl-carbonic acid menthyl ester {[α]_D²⁵ = -36.7 (c = 0.5 chloroform)} prepared according to step 1 are dissolved in a mixture of 20 ml of 10% by weight sulfuric acid and 20 ml of ethanol and the solution is heated to boiling for 24 hours, whereupon the ethanol is removed in vacuo. To the aqueous residue about 30 ml of benzene are added and the mixture is evaporated again to dryness in vacuo. This operation is carried out five or six times. The residue is suspended in 30 ml of chloroform and the pH is adjusted to a value of about 10 by adding a concentrated ammonium hydroxide solution. The layers are separated, the chloroform solution is washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is purified by column chromatography (Merck 9385 silicagel, water pump vacuo; eluent : chloroform : methanol = 20:1). The fractions containing the desired compound are combined and evaporated. The residue is crystallized from ether. Thus 32 mg of the desired compound are obtained, mp.: 190-194°C, [α]_D²⁵ = +63.9° (c = 0.5, chloroform).

Further steps

The (+)-1α-[nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4β-ol was converted into the corresponding epibatidine by working analogously to Example 1 starting with reacting the former instead of (±)-1α-[nitro]-2β-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4β-ol in the description of the preparation of the starting substance of Example 1, section f).

Example 5

A)

(-)-Epibatidine and (+)-epibatidine dihydrochloride

Step 1

(+)-Epi-epibatidine and (+)-epi-epibatidine dihydrochloride

1.00 g (5 millimoles) of racemic epi-epibatidine prepared according to Example 1 or 2 are dissolved in 20 ml of hot acetone, whereupon a solution of 0.96 g (2.5 millimoles) of (-)-di-0,0'-p-toluoyl-L-tartaric acid in a mixture of 20 ml of acetone and 10 ml of water is added. The solution remains clear for some minutes but later the precipitation of crystals starts from the hot solution. The mixture is allowed to cool to room temperature and allowed to stand overnight in a refrigerator. Next morning the precipitated crystals are filtered, washed with a mixture of 5 ml of acetone and 1 ml of water and dried. Thus 1.053 g of the salt are obtained. Mp.: 188-190°C, [α]_D²⁵ = -56.9° (c = 0.5, methanol).
1.00 g of the above salt is dissolved in a hot mixture of 100 ml of ethanol and 5 ml of water and the solution is allowed to stand at room temperature for a week-end. The precipitated crystals are filtered, washed with a mixture of 5 ml of ethanol and 0.5 ml of water and dried. Thus 341 mg of the salt are obtained, mp.: 200-201°C, [α]_D²⁵ = -53.4° (c = 0.5, methanol).
300 mg of the above salt are suspended in a mixture of 120 ml of chloroform and 8 ml of water at room temperature and sufficient amount of a 1 molar sodium hydroxide solution (about 0.2-0.3 ml) is added to adjust the pH of the aqueous phase to 9-10. The layers are separated, the chloroform solution is washed twice with 8 ml of water each, dried over sodium sulfate, filtered and evaporated in vacuo. Thus 155 mg of an oily product are obtained, [α]_D²⁵ = +36.1° (c = 0.5, methanol).

Step 2

(-)-Epibatidine and (+)-epibatidine dihydrochloride

On epimerizating the (+)-epi-epibatidine prepared according to step 1 analogously to Example 1, step 2 (-)-epibatidine is obtained which is converted into the hydrochloride. The rotation of the salt {[α]_D²⁵ = +34.8° (c = 0.36, methanol)} corresponds to the value {[α]_D²⁵ = +34.7° (c = 0.36, methanol)} disclosed in the Prior Art (S.R. Fletscher et al., J. Chem. Soc. Chem. Column. [1993], 1216).

B)

(+)-Epibatidine

Step 1

(-)-Epi-epibatidine

The first crystallization mother-lye obtained by the preparation of (+)-epi-epibatidine under section A) is evaporated to dryness in vacuo and the crystalline residue is made water-free by evaporation on a rotating evaporator several times. Thus 649 mg of the product are obtained, mp.: 164-176°C, [α]_D²⁵ = -64.8° (c = 0.5, methanol).
200 mg of the above salt are suspended in a mixture of 80 ml of chloroform and 6 ml of water. The pH is adjusted to 9-10 by adding a 1 molar sodium hydroxide solution. The layers are separated, the chloroform solution is washed with water (about 10 ml), dried over sodium sulfate, filtered and evaporated to dryness. Thus 96 mg of an oily product are obtained, [α]_D²⁵ = -17.2° (c = 0.5, methanol).
400 mg of the above salt {[α]_D²⁵ = -64.8° (c = 0.5, methanol)} are treated with 2 ml of a 1 M sodium hydroxide solution in a mixture of 150 ml of chloroform and 10 ml of water. The reaction mixture is worked up. 160 mg of an oily product are obtained. [α]_D²⁵ = -17.2° (c = 0.5, methanol).
The oily crude product thus obtained (160 mg, 0.76 millimoles) is dissolved in 3.2 ml of hot acetone, whereupon a solution of 153 mg (0.396 millimole) of (+)-di-0,0'-p-toluoyl-D-tartaric acid, 3.2 ml of acetone and 0.6 ml of water is added. The reaction mixture is allowed to cool to room temperature, allowed to stand for a few hours, the precipitated crystals are filtered, washed with some drops of aqueous acetone and dried. Thus 269 mg of the salt are obtained, mp.: 196-198°C, [α]_D²⁵ = +63.4° (c = 0.5, methanol).
200 mg of the above salt are recrystallized from a mixture of 4.5 ml of ethanol and 0.5 ml of water. Thus 124 mg of the pure salt are obtained, mp.: 204-205°C, [α]_D²⁵ = +60.3°, (c = 0.5, methanol).
100 mg of the salt thus obtained are treated with 2 ml of a 1 M sodium hydroxide solution in a mixture of 40 ml of chloroform and 4 ml of water. Thus 60 mg of an oily product are obtained, [α]_D²⁵ = -40.3° (c = 0.5, methanol).

Step 2

(+)-Epibatidine

On epimerizating the (-)-epi-epibatidine prepared according to step 1 analogously to Example 1, step 2 (+)-epibatidine is obtained. This could be converted into the (-)-epibatidine hydrochloride.

Claims

Process for preparing racemic or optically active epibatidine of formula
characterized by
a) subjecting racemic or optically active epi-epibatidine of formula
to epimerization in the presence of a base or

b)
α) cyclising a racemic or optically active 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula
wherein
L stands for a leaving group, particularly a C₁₋₄-alkylsulfonyloxy or arylsulfonyloxy group
to racemic or optically active epi-epibatidine of formula XIII
and thereafter

β) subjecting the latter to epimerization in the presence of a base
or

c)
α) selectively reducing the nitro group of 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula
to yield 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula

β) protecting the carbonyl group in the latter, preferably to yield a 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula
wherein
R₁ and R₂ stand for C₁₋₄-alkyl groups or together form a C₂₋₄-alkylene group,

γ) diacylating the amino group of the latter, preferably to yield a 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula
wherein
R₁ and R₂ stand for C₁₋₄-alkyl groups or together form a C₂₋₄-alkylene group and

Ac represents an acyl group,

δ) deprotecting the oxo group of the latter to yield a 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of general formula
wherein
Ac stands for an acyl group,

ε) exchanging in the latter the oxo group for an amino group to yield a 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-4-[amino]-cyclohexane of general formula
wherein
Ac stands for an acyl group,
and

ω) cyclizing the latter into epibatidine of formula XIV
or

d) cyclizing 1-[6'-(chloro)-pyrid-3'-yl]-3-[oxo]-6-[nitro]-hexa-1-ene of formula
in the presence of an optically active base to optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV
and thereafter

d₁)
α) selectively reducing the optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV thus obtained to yield optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula

β) introducing into the latter a leaving group to yield an optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula
wherein
L represents a leaving group, particularly a C₁₋₄-alkylsulfonyloxy or arylsulfonyloxy group,

γ) reducing the latter to an optically active 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula

δ) cyclising the latter to an optically active epi-epibatidine of formula XIII
and

ε) subjecting the latter to epimerization in the presence of a base
or

d₂) converting the optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV into an optically active epibatidine of formula XIV analogously to variant c)
and, in a manner known per se if desired, resolving a racemic epibatidine of formula XIV into the optically active isomers and/or racemising the optically active isomers or, if desired, separating a racemic intermediate product in any stage of the synthesis into the optically active isomers and converting the optically active isomers thus obtained into optically active epibatidine of formula XIV.
Process according to claim 1a) or b)β), characterized by carrying out epimerization at an elevated temperature.
Process according to claims 1a), or b)β) or 2, characterized by using for the epimerization an alkaly alcoholate or another organic alkali compound.
Process according to claims 1a) or b)β), 2 or 3, characterized by using for the epimerization as base potassium tertiary butylate, sodium ethylate or lithium diisopropyl amine.
Process according to claims 1a) or b)β) or 2 to 4, characterized by carrrying out the epimerization in the presence of an alkali alcoholate under heating and the epimerization in the presence of another organic alkali compound at a temperature of about 0°C.
Process according to claims 1a) or b)β) or 2 to 5, characterized by carrying out the epimerization in a C₁₋₄-alkanol as medium in the presence of an alkali alcoholate corresponding to the alkanol used as solvent.
Process according to claim 1b), characterized by cyclising a 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula I, in which the leaving group represented by L is a methanesulfonyloxy, p-toluenesulfonyloxy or p-(bromo)-phenylsulfonyloxy group.
Process according to claim 1b) or 7 characterized by cyclising the 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane, 4-substituted by a leaving group, of general formula I at an elevated temperature, particularly at the boiling point of the reaction mixture.
Process according to claim 1b), 7 or 8, characterized by carrying out the cyclization in an aprotic solvent, particularly in a halogenated hydrocarbon or an aromatic hydrocarbon or a mixture thereof.
Process according to claims 1b) or 7 to 9, characterized by carrying out the cyclization in benzene, toluene and/or xylene as aprotic solvent(s).
Process according to claim 1c), characterized by carrying out the selective reduction of the nitro group of 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV by catalytic hydrogenation or reduction with a chemical agent.
Process according to claim 1c) or 11, characterized by carrying out the selective reduction of the nitro group of 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula IV by Bechamps reduction, or with zinc in glacial acetic acid or with zinc, iron or tin in hydrochloric acid or with stannous(II)-chloride.
Process according to claim 1c), characterized by carrying out the protection of the carbonyl group of 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of formula XIX in the form of an ethylene ketale.
Process according to claim 1c), characterized by diacylating the amino group of the 1-[amino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula XV is carried out to yield a 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula XVI, in which Ac stands for C₁₋₄-alkylsulfonyl or arylsulfonyl, particularly methanesulfonyl, p-toluenesulfonyl or p-(bromo)-phenylsulfonyl.
Process according to claim 1c), characterized by carrying out the deprotection of the oxo group of the 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one ketal of general formula XVI by acidic treatment.
Process according to claim 1c), characterized by carrying out the exchange of the oxo group of the 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-one of general formula XVII for an amino group by reduction with a complex metal hydride in the presence of ammonium acetate.
Process according to claim 1c) or 16, characterized by using for the exchange of oxo group for amino group lithium cyano borohydride and/or sodium cyanoborohydride as complex metal hydride(s).
Process according to claim 1c), characterized by carrying out the cyclization of the 1-[diacylamino]-2-[6'-(chloro)-pyrid-3'-yl]-4-[amino]-cyclohexane of general formula XVIII by heating in [an] organic solvent(s).
Process according to claim 1c) or 18, characterized by using for the cyclization as organic solvent(s) [an] anhydrous dipolar aprotic solvent(s), most preferably dimethyl formamide.
Process according to claim 1c), 18 or 19, characterized by carrying out the cyclization in the presence of sodium borohydride.
Process according to claim 1d), characterized by using for the cyclization (+)-α-(phenyl)-ethyl-amine or (-)-α-(phenyl)-ethyl-amine as optically active base.
Process according to claim 1, characterized by resolving the racemic 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula III and thereafter converting the optically active 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula III into optically active epibatidine of formula XIV.
Process according to claim 1 or 22, characterized by carrying out the resolving of the racemic 1-[nitro]-2-[6'-(chloro)-pyrid-3'-yl]-cyclohexane-4-ol of formula III by esterifying it with optically active menthyl chloro formiate, separating the diastereomers thus obtained by crystallization and thereafter removing the menthyl group.